Drug delivery system based on polyethylene vinylacetate copolymers

ABSTRACT

A drug delivery system consisting of one or more compartments and comprising a progestogenic compound dissolved in a thermoplastic polyethylene vinylacetate copolymer whereby,
         if the delivery system consists of one compartment, the compartment comprises       (i) a core of a thermoplastic polyethylene vinylacetate copolymer comprising the progestogenic compound, such progestogenic compound being dissolved in the polyethylene vinylacetate copolymer up to a concentration below the saturation level at 25° C., and an estrogenic compound; and   (ii) a skin of a thermoplastic polyethylene vinylacetate copolymer covering the core, said skin being permeable for both compounds;
       if the delivery system consists of more than one compartment, only one compartment comprises   
       (iii) the progestogenic compound, such progestogenic compound being dissolved in a core of a thermoplastic polyethylene vinylacetate copolymer up to a concentration below the saturation level at 25° C., and an estrogenic compound; and   (iv) a skin of a thermoplastic polyethylene vinylacetate copolymer covering the core, said skin being permeable for both compounds.

FIELD OF THE INVENTION

The present invention relates to the field of female contraception andhormone replacement therapy.

The invention relates to a drug delivery system, its manufacture and itsuse, to make a kit or a combination preparation.

BACKGROUND TECHNOLOGY

Drug delivery systems, especially those intended for intravaginal useare known in the art.

U.S. Pat. No. 3,995,633 and U.S. Pat. No. 3,995,634 describe separate,preferably spherical or cylindrical, reservoirs containing differentactive substances, which are assembled in specially constructed holders.

U.S. Pat. No. 4,237,885 describes a tube or coil of polymeric materialwhich is divided into portions by means of a plurality of “spacers”provided in the tube, after which each of the separate tube portions isfilled with a different active substance in a silicone fluid and the twoends of the tube are subsequently connected to one another. In thisrelease system, however, transport (diffusion) of active material fromone reservoir to the other takes place through the wall of the tube,especially upon prolonged storage, so that the pre-set fixed releaseratio between the active substances in question will change over aperiod of time.

EP-A-0050867 discloses a two-layered vaginal ring which comprises apharmacologically acceptable supporting ring covered by two layerspreferably of silicone elastomers whereby the inner layer is a siliconeelastomer loaded with an active substance.

A ring-shaped silicone vaginal delivery system has been described inU.S. Pat. No. 4,292,965. The use of silicone elastomers is nowadaysconsidered to be less safe and is clearly no longer the material ofchoice.

U.S. Pat. No. 4,596,576 describes a two-compartment vaginal ring whereineach compartment contains a different active substance. To achieve asuitable ring with a constant release ratio between the various activesubstances, the end portions of the compartments are joined by glassstoppers.

Drug delivery systems for intravaginal use, and in particular vaginalrings, prepared of polyethylene vinylacetate (EVA) copolymers are alsoknown in the art.

For example, J. A. H. van Laarhoven et al., International Journal ofPharmaceutics 232 (2002) pages 163-173, describes the use of EVAcopolymers for the preparation of a vaginal ring.

WO-A-97/02015 describes a two-compartment device: a first compartmentconsisting of an EVA copolymer core, an EVA copolymeretonogestrel-loaded middle layer and an EVA copolymer non-medicatedouter layer; and a second compartment consisting of an EVA copolymercore, loaded with both etonogestrel and ethinyl estradiol, and an EVAcopolymer non-medicated outer layer. The preparation of thetwo-compartments device requires the cutting of fibres in the requiredlengths and the assembly of the pieces to a ring-shaped device.

EP-A-876815 describes a one-compartment vaginal ring comprising an EVAcopolymer core comprising ethinyl estradiol and etonogestrel; and anon-medicated EVA copolymer skin. The progestogenic steroid etonogestrelis dissolved in the EVA copolymer core material in a concentration abovethe saturation level.

Among the above disclosures, EP-A-876815 clearly sets a standard; itinvolves a one-compartment design, it obviates the need for silasticpolymer by using EVA combinations, and it releases two or more activesubstances in a substantially constant ratio to one another over aprolonged period in time.

Although the vaginal ring described in EP-A-876815 fulfills its purposeand provides contraception, the design can still be improved upon. Thedrug delivery device disclosed in EP-A-876815 is physically stable onlywhen stored below room temperature. It requires storage and transportbelow room temperature, which is expensive and requires a lot ofattention. As indicated in EP-A-876815 the progestogen may eventuallycrystallize out on the exterior surface of the vaginal ring. Such acrystallization of progestogen onto the skin of the device may lead touncontrolled and high burst release.

It is therefore desirable to avoid the possibility of crystallization ofthe progestogen on the exterior surface of the vaginal ring when it isstored on or above room temperature (i.e. about 25° C.). At the sametime, however, the amounts of progestogen released and release rateshould remain unchanged, to ensure a sufficient pharmaceutical effectfor use in contraception and/or Hormone Replacement Therapy (HRT).

An improved drug delivery device, easy to prepare, whilst avoiding thepossibility of exterior crystallization of the progestogenic compoundand still providing sufficient amounts and rates of release of theprogestogenic compound for use in contraception and/or HRT has now beenfound.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides a drug delivery systemconsisting of one or more compartments and comprising a progestogeniccompound dissolved in a thermoplastic polyethylene vinylacetatecopolymer whereby,

-   -   if the delivery system consists of one compartment, the        compartment    -   comprises        (i) a core of a thermoplastic polyethylene vinylacetate        copolymer comprising the progestogenic compound, such        progestogenic compound being dissolved in the polyethylene        vinylacetate copolymer up to a concentration below the        saturation level at 25° C., and an estrogenic compound; and        (ii) a skin of a thermoplastic polyethylene vinylacetate        copolymer covering the core, said skin being permeable for both        compounds;    -   if the delivery system consists of more than one compartment,        only one compartment comprises        (iii) the progestogenic compound, such progestogenic compound        being dissolved in a core of a thermoplastic polyethylene        vinylacetate copolymer up to a concentration below the        saturation level at 25° C., and an estrogenic compound; and        (iv) a skin of a thermoplastic polyethylene vinylacetate        copolymer covering the core, said skin being permeable for both        compounds.

The improved drug delivery system is physically stable under roomtemperature conditions (about 25° C.) and thus does not need specialstorage and transportation conditions at a temperature below roomtemperature. Moreover the drug delivery system is easy to prepare andstill provides sufficient amounts and rates for release of theprogestogenic compound for use in contraception and/or HRT.

FIG. 1:

In-vitro release rates of etonogestrel for a number of drug deliverysystems described in examples 2-14 according to the invention and twocomparative examples.

FIG. 2:

Curve fit of the vinyl acetate content of polyethylene vinylacetatecopolymers summarized in Table II versus the saturation level ofetonogestrel in these same copolymers at 25° C. and at 37° C.

DETAILED DESCRIPTION OF THE INVENTION

The advantages of the invention are obtained by designing the drugdelivery system as described above. The drug delivery system comprisesat least one compartment, which consists of two layers, i.e. a core anda skin. The skin is directly covering the core, giving the drug deliverysystem an uncomplicated design such that it can be prepared by aneconomically attractive preparation process.

In one embodiment the progestogenic compound is present in aconcentration such that the core comprises the progestogenic compoundbeing dissolved in the polyethylene vinylacetate copolymer up to aconcentration below the saturation level at 25° C. In another embodimentthe concentration of the progestogenic compound below the saturationlevel at 25° C. in the core can be obtained by using polyethylenevinylacetate copolymer with a relatively high concentration ofvinylacetate, that is, a copolymer containing in the range from 30 to 50wt % vinylacetate copolymer. In a further embodiment the polyethylenevinylacetate copolymer in the core comprises in the range from 32 to 45wt % vinylacetate. Use of such a polyethylene vinylacetate copolymerwith a relatively high concentration of vinylacetate was found to resultin decreased release of progestogenic compound from the core.

In one embodiment polyethylene vinylacetate copolymer has a wt %vinylacetate of 32 to 50% and in an even further embodiment has a wt %vinylacetate of 35 to 50%. The use of a polyethylene vinylacetatecopolymer having such a high vinylacetate content for the core providesa system with an advantageous flexibility.

In another embodiment the skin is prepared from polyethylenevinylacetate copolymer comprising 1 to 15 wt % vinylacetate, and in aneven further embodiment from polyethylene vinylacetate copolymercomprising 5 to 15 wt % vinylacetate.

In an even further embodiment a polyethylene vinylacetate content in therange of 1 to 15 wt % can advantageously be used in a drug deliverysystem having a skin with a thickness in the range from 10 to 110 μm.Such a skin thickness of less than about 110 μm is advantageous toobtain a good flexibility of the overall pharmaceutical delivery device.Furthermore the use of such skin thickness and vinylacetate contentresults in an advantageous low burst release.

In another embodiment polyethylene vinylacetate copolymer has avinylacetate content of 14 to 28 wt % for the skin. Such vinylacetatecontent can advantageously be used in a pharmaceutical delivery devicehaving a skin thickness in the range from 70 to 250 μm, for which it isespecially easy to obtain a very good process consistency. A skin ofpolyethylene vinylacetate copolymer with a vinylacetate content of about14 to 28 wt % is further advantageous, because it results in anadvantageously low extent of aging of the material. Such aging can bechemical or physical. It is herein noticed that, without wishing to bebound to any kind of theory, aging can result in a gradual change intime of the release profile (properties) due to physical changes in thepolymeric structure of the copolymer. The above embodiment thus resultsin an advantageously low extent of change of the release profile of theactive ingredients after long-term storage.

The polyethylene vinylacetate copolymer can independently for core andskin be any commercially available polyethylene vinylacetate copolymer,such as for example the products available under the trade names:Elvax®, Evatane®, Lupolen V®, Movriton®, Ultrathene®, Ateva® andVestypar® and further polyethylene vinylacetate copolymers marketed byfor example Dupont (e.g. Dupont 760), Equistar (e.g. EquistarUE637-000), Huntsman (e.g. Huntsman PE1903) and Exxon Mobil (F100309).Suitable polyethylene vinylacetate copolymers for the core include thecommercially available Ateva® 4030, Ateva® 3325, Evatane® 33-25 andEvatane® 40-55. Suitable polyethylene vinylacetate copolymers for theskin include the commercially available Ateva® 1070, Ateva® 1231 enAteva® 1525 Evatane® 1020 VN3, Evatane® 1040 VN4 and Evatane® 1080 VN5.

The progestogenic compound of the subject invention can be anyprogestogen. In a further embodiment, the progestogenic compound is asteroidal progestogenic compound. Examples of suitable progestogeniccompounds include compounds such as desogestrel, etonogestrel,levonorgestrel, norgestimate, gestodene, drospirenone or any othercompound with progestogenic activity. In a particular embodiment theprogestogenic compound is etonogestrel (3-keto desogestrel).

In a further embodiment, when the progestogenic compound isetonogestrel, such etonogestrel is present in the core in aconcentration below the saturation level at 25° C. between 0.1 and 1.0wt %, based on the weight of the core, and in an even further embodimentin a concentration between 0.3 and 0.8 wt %. In a particular embodimentsuch etonogestrel is present in the core in a concentration in the rangeof 0.4 to 0.7 wt %.

The estrogenic compound can be any estrogen. In a further embodiment,the estrogenic compound is a steroidal estrogenic compound. Examples ofsuitable estrogenic compounds include compounds such as estradiol,estriol, mestranol, estradiol-valerate and ethinyl estradiol. In aparticular embodiment the estrogenic compound is ethinyl estradiol. In afurther embodiment such ethinyl estradiol is present in the core in aconcentration between 0.01 and 0.5 wt %, based on the weight of thecore, and in an even further embodiment in a concentration between 0.05and 0.2 wt %. In a particular embodiment such ethinyl estradiol ispresent in the core in a concentration in the range of 0.07 to 0.15 wt%.

In addition to the progestogenic compound and the estrogenic compoundthe drug delivery system can contain other drugs, e.g. anti-microbials.Such anti-microbials can be used for example to concomitantly treatand/or prevent sexually transmitted diseases (STD's) such as AIDS,chlamydia, herpes and gonorrhoea. The anti-microbial drug can be anyanti-bacterial drug such as any antibiotic, any anti-viral agent, anyanti-fungal agent or any anti-protozoal agent. An example of ananti-microbial drug contemplated to be incorporated into the vaginalring of the subject invention is mandelic acid condensation polymer(Zanefeld et al. (2002), Fertility and Sterility 78(5): 1107-1115).Another example is dapivirine(4-[[4-[2,4,6-trimethylphenyl)amino-2-pyrimidinyl]amino]benzonitrile).

The improved drug delivery system according to the invention providessufficient amounts and rates of release of the progestogenic compoundfor use in contraception and/or HRT. By these sufficient amounts andrates for release is understood that throughout the release period ateach point in time a safe and sufficient effective amount of theprogestogenic compound is released. In particular the release profile ofthe progestogenic compound may not be too steep. The mean releaserequired is dependent on the use. In an even further embodiment for usein contraception the mean release may also not be too low. In onepractical embodiment, when the progestogenic compound is etonogestrel,sufficient amounts and rates of release of etonogestrel for use incontraception are amounts and rates of release similar to those ofNuvaring®. In one embodiment the release of etonogestrel of such a drugdelivery device on day 21 (R₂₁) is 80 μg/day or more. In a furtherembodiment the mean release of etonogestrel of such a drug deliverydevice lies in the range from 96 to 144 μg/day. In a further embodiment,the release of etonogestrel in such a drug delivery device is reflectedby releases at R₂ and/or R₂₁, wherein R₂ lies in the range from 122-181μg/day; and/or R₂₁ lies in the range from 82 to 121 μg/day. In an evenfurther embodiment, the release of etonogestrel in such a drug deliverydevice is reflected by releases at R₂ and/or R₂₁, wherein R₂ lies in therange from 135-165 μg/day; and/or R₂₁ lies in the range from 85 to 115μg/day. In a still even further embodiment, the release of etonogestrelin such a drug delivery device is reflected by releases at R₂ and/or R₂₁wherein R₂ lies in the range from 140-160 μg/day; and/or R₂₁ lies in therange from 90 to 110 μg/day. In an even further embodiment, when theprogestogenic compound is etonogestrel, R₂ is about 150 μg/day dayand/or R₂₁ is about 100 μg/day.

In one embodiment the drug delivery system according to the invention isa cylindrical fibre, consisting of a cylindrical core and a skincovering this core. In a particular embodiment the cross sectionaldiameter of such a cylindrical fibre is between about 2.5 and 6 mm, in aspecific embodiment between about 3.0 and 5.5 mm, and in anotherembodiment between about 3.5 and 4.5 mm and in yet another embodiment is4.0 or 5.0 mm. In one embodiment, the surface of the core body is morethan 800 mm², and in another embodiment more than 1000 mm² and in afurther embodiment in the order of 1700-2200 mm². Significantly largersurfaces are possible, provided that the design (physical dimensions) ofa drug delivery system intended for vaginal use prevents inconveniencefor the subject.

The drug delivery system according to the invention can have severalshapes, including but not limited to a spiral shape, a T-shape or a ringshape. In a specific embodiment the drug delivery system according tothe invention is ring-shaped, i.e. is an annular drug delivery system.In one particular embodiment, the drug delivery system is a ring-shapeddrug delivery system having an outer circumference of the ring ofbetween 50 and 60 mm and in another embodiment between 52 and 56 mm.

The drug delivery system comprises at least one compartment having thecharacteristics as specified in the claims. In addition to thiscompartment one or more additional compartments can be present, making atotal of for example two or three compartments. For example, anadditional compartment can be added which is a placebo compartment or acompartment loaded with one or more other drugs. Such an extracompartment can be advantageous for example in practicing hormonalreplacement therapy, where the ratio between progestogen and estrogen isdifferent from the ratio suitable for contraception. Such an extracompartment can also be advantageous to administer, in addition to theprogestogenic and estrogenic compounds, anti-microbial drugs to treatand/or prevent STD's such as AIDS, chlamydia, herpes and gonorrhoea, assuggested hereinabove.

In a specific embodiment, however, the drug delivery system consists ofonly one compartment, such compartment having the characteristics asspecified in the claims.

In one specific embodiment the drug delivery system consisting of one ormore compartments and comprising a progestogenic compound dissolved in athermoplastic polyethylene vinylacetate copolymer whereby,

-   -   if the delivery system consists of one compartment, the        compartment comprises        (i) a core of a thermoplastic polyethylene vinylacetate        copolymer, said copolymer containing 30 to 50 wt % vinylacetate,        and said core comprising a progestogenic compound, said        progestogenic compound being dissolved in the polyethylene        vinylacetate copolymer up to a concentration below the        saturation level at 25° C., and an estrogenic compound; and        (ii) a skin of a thermoplastic polyethylene vinylacetate        copolymer covering the core, said copolymer containing 1 to 15        wt % vinylacetate, said skin being permeable for both compounds,        and said skin having a thickness in the range of 10 to 110 μm;    -   if the delivery system consists of more than one compartment,        only one compartment comprises        (iii) the progestogenic compound, such progestogenic compound        being dissolved in a core of a thermoplastic polyethylene        vinylacetate copolymer up to a concentration below the        saturation level at 25° C., said copolymer containing 30 to 50        wt % vinylacetate, and an estrogenic compound; and        (iv) a skin of a thermoplastic polyethylene vinylacetate        copolymer covering the core, said copolymer containing 1 to 15        wt % vinylacetate, said skin being permeable for both compounds,        and said skin having a thickness in the range of 10 to 110 μm.

In a further embodiment the concentration of progestogenic compound inthe core lies in the range of 0.3 to 0.8 wt %.

In an even further embodiment said skin has a thickness in the range of20 to 100 μm. In a still further embodiment said skin has a thickness inthe range of 30 to 70 μm. In a still even further embodiment thecopolymer of the skin contains 1 to 14 wt % vinylacetate. In an evenfurther embodiment the copolymer of the skin contains 1 to 12 wt %vinylacetate. Such drug delivery system has the further advantage thatan advantageous low burst release can be obtained.

In another specific embodiment of the invention the drug delivery systemconsisting of one or more compartments and comprising a progestogeniccompound dissolved in a thermoplastic polyethylene vinylacetatecopolymer whereby,

-   -   if the delivery system consists of one compartment, the        compartment comprises        (i) a core of a thermoplastic polyethylene vinylacetate        copolymer, said copolymer containing 30 to 50 wt % vinylacetate,        and said core comprising a progestogenic compound, such        progestogenic compound being dissolved in the polyethylene        vinylacetate copolymer up to a concentration below the        saturation level at 25° C., and an estrogenic compound; and        (ii) a skin of a thermoplastic polyethylene vinylacetate        copolymer covering the core, said copolymer containing 14 to 28        wt % vinylacetate, said skin being permeable for both compounds,        and said skin having a thickness of 70 to 250 μm;    -   if the delivery system consists of more than one compartment,        only one compartment comprises        (iii) the progestogenic compound, such progestogenic compound        being dissolved in a core of a thermoplastic polyethylene        vinylacetate copolymer up to a concentration below the        saturation level at 25° C., said copolymer containing 30 to 50        wt % vinylacetate, and an estrogenic compound; and        (iv) a skin of a thermoplastic polyethylene vinylacetate        copolymer covering the core, said copolymer containing 14 to 28        wt % vinylacetate, said skin being permeable for both compounds,        and said skin having a thickness of 70 to 250 μm.

In a further embodiment the concentration of progestogenic compound inthe core lies in the range of 0.3 to 0.8 wt %. In a still furtherembodiment the thickness of said skin is in the range from 75 to 250 μm,and in an even further embodiment the thickness of said skin is in therange from 80 to 180 μm. In a still further embodiment the thickness ofsaid skin is 100 to 250 μm. And in a further embodiment the thickness ofsaid skin is 110 to 250 μm. In an even further embodiment thevinylacetate content of the thermoplastic skin lies in the range from 14to 28 wt % vinylacetate. And in a still further embodiment thevinylacetate content of the skin is from 16 to 25 wt %.

Such drug delivery system shows an improved stability in that therelease profile is less and in some cases not or nearly not influencedby the aging of the skin copolymer.

The drug delivery system of the subject invention can be manufactured byany known process of extrusion, such as co-extrusion and/orblend-extrusion. For example, the drug-loaded core and the non-medicatedouter layer can be co-extruded. The fibres thus obtained can be cut intopieces of the required length and each piece can be assembled to, forexample, a ring-shaped device in any suitable manner. In one embodimentthe fibres are cut into pieces with a length in the range from 135 to185 mm and in a further embodiment into pieces with a length in therange 155 to 159 mm, and in one further embodiment into pieces with alength of about 157 mm. Subsequently the pieces are assembled into aring-shaped device. The assembly into a ring-shaped device can becarried out in any manner suitable for this purpose. For example theends of the fibre can be joined together with an adhesive; or by placingthe fibre in a mould at an elevated temperature (e.g. a temperature ofabove about 40° C.) and injecting molten high density polyethylene inbetween the fibre ends, whereafter the prepared ring is cooled; or byjoining the fibre ends together by welding. In one embodiment aring-shaped drug delivery system is prepared by welding the fibre endstogether at a welding temperature of 130° C. and a welding time of 15 to20 seconds, on a TWI mono-welding unit.

The present invention hence also provides a method of manufacturing adrug delivery system in the shape of a ring comprising the steps of:

-   (i) producing a medicated homogenous polyethylene vinylacetate    copolymer core granulate, comprising a progestogenic and an    estrogenic compound;-   (ii) co-extruding the core granulate with a polyethylene    vinylacetate copolymer skin granulate, resulting in a copolymer    fibre comprising a core covered by a skin;-   (iii) assembling the fibre into a ring.

As indicated above the loaded (medicated) homogenous polymer can be asuitable polyethylene vinylacetate copolymer loaded with a suitableprogestogenic compound and a suitable estrogenic compound. The polymerfor the skin can be another suitable polyethylene vinylacetatecopolymer.

The thermoplastic polyethylene vinylacetate copolymer core granulate canbe prepared by grounding the polyethylene vinylacetate copolymer for thecore; dry powder mixing the grounded polymer for the core with theprogestogenic and/or estrogenic compound to be loaded in the core; blendextruding the resulting powder mixture; and cutting the resulting loadedpolymer strands into granules, thereby obtaining a core granulate. Thecore granulate can be lubricated with a lubricant. Suitable lubricantsinclude for example irgawax, talc, aerosil and stearates such asmagnesium stearate.

The prepared rings can for example be packed in a suitable sachet, suchas described in e.g. EP-A-1037812, optionally after being sterilized ordisinfected.

The drug delivery system according to the invention is especiallysuitable for use in the field of female contraception and hormonereplacement therapy. The drug delivery system can advantageously be usedfor the simultaneous controlled release of a progestogenic compound andestrogenic compound. The drug delivery system may—as already indicatedabove—also be used to concomitantly provide contraception and combatmicrobial disease. The microbial infection to be treated and/orprevented can be any bacterial, viral, fungal or protozoal infection.Specifically, sexually transmitted diseases such as HIV, chlamydia,gonorrhoea, or herpes may be treated by incorporation of ananti-microbial agent into the ring of the subject invention.

The invention further provides a method of contraception which comprisesthe steps of a) positioning a drug delivery system of the subjectinvention within the female vaginal tract and b) retaining the systemwithin the vaginal tract for at least approximately 21 days. In additionthe invention provides a method of concomitantly providing contraceptionwhilst simultaneously treating or preventing a sexually transmitteddisease which comprises the steps of positioning a drug delivery systemof the subject invention within the female vaginal tract and retainingthe system within the vaginal tract for at least approximately 21 days.

In one embodiment, the drug delivery system is removed after about 21days for an approximate one week period to permit menstruation. In otherembodiments, the drug delivery system is removed after about 42, 63, 84,105, 126, 147, 186, 189, 210, 231, 252, 273, 294, 315, 336 or 357 daysor after each month for an approximate one week period to permitmenstruation. After the approximate week to allow for menstruation, anew drug delivery system of the subject invention is inserted into thefemale vagina to provide contraception in the next female cyclus orcycli.

In another embodiment, the drug delivery system is removed after about21 days and a subsequent drug delivery system is inserted directly afterthe previous drug delivery system has been removed, i.e. without anapproximate one week period to permit menstruation. In otherembodiments, the drug delivery system is removed after about 42, 63, 84,105, 126, 147, 186, 189, 210, 231, 252, 273, 294, 315, 336 or 357 daysor after each month.

In a further embodiment this invention provides the use of the drugdelivery system described above for the manufacture of a contraceptivekit or kit for hormone-replacement therapy.

In a still further embodiment this invention provides the use of thedrug delivery system described above for the manufacture of acombination preparation to provide contraception whilst simultaneouslyto treat and/or prevent a sexually transmitted disease.

The invention is further illustrated by the following non-limitingexamples.

Preparation of the Examples

Examples of ring-shaped drug delivery systems, comprising thepolyethylene vinylacetate copolymer materials for skin and core, thedimensions and the concentrations of active ingredients as indicated inTable I, were prepared as follows:

Etonogestrel (a progestogenic compound) and ethinyl estradiol (anestrogenic compound) were mixed homogeneously through the copolymer usedfor the core.

The mixing of the core material of examples 1-10 was performed by drypowder mixing the micronized compounds and copolymer powder in astainless steel drum using a Rhönrad (Barrel-hoop principle) with afixed rotation speed of approximately 46 rpm for 15 minutes.

The mixing of the core material of examples 12-14 was performed by drypowder mixing the micronized compounds and copolymer powder in astainless steel drum using a Rhönrad (Barrel-hoop principle) with afixed rotation speed of approximately 26 rpm for 60 minutes.

For preparing the core material of example 11, the micronized compoundswere mixed with copolymeric granulate instead of powder. Mixing wascarried out in a stainless steel drum using a Rhönrad (Barrel-hoopprinciple) with a fixed rotation speed of approximately 26 rpm for 60minutes.

Subsequently the homogenized mixture was blend extruded using a 25 mmco-rotating double screw blend extruder and the resulting medicatedpolymer strands were cut into granules using an Scheer granulator.According to this process a drug-loaded core granulate was manufactured.

After granulation the drug-loaded core granulate for examples 11-14 wassieved. The drug-loaded core granulate for all examples was lubricatedwith magnesium stearate in order to facilitate the next processing step(co-extrusion). In examples 1-10 the drug loaded core granulate wasco-extruded with the copolymer used for the skin in a PlasticMachinenbau co-extruder. In examples 11-14 the drug loaded coregranulate was co-extruded with the copolymer used for the skin in aFourne 35-22 co-extruder. The skin and core materials were combined in aself-centering spinning block from which two co-extruded fibres wereproduced. For each fibre, 2 separate spinning pumps (to control thevolume flow rate (melt flow) of each layer) were applied. Thecapillaries applied had a diameter of 3.6 mm and all fibres wereextruded at an extrusion temperature of 110° C.

The drug loaded fibers of examples 1-10 were processed at an extrusionspeed of 1 m/min; the drug loaded fibres of examples 12-14 wereprocessed at an extrusion speed of 6.7 m/min; and the drug loaded fiberof example 11 was processed at an extrusion speed of 2.0 m/min

Upon leaving the spinnerette, the skin-core fibre was led through airand subsequently through a water bath (10-20° C.) by means of a take-offunit. The outer diameter of the fibre was measured on-line continuouslyusing a laser micrometer. Hereafter the fibres were cut into pieces ofabout 157 mm. For examples 1-10 the ends of the fibre pieces weresubsequently glued together with Loctite® acrylate glue. The ends of thefibre pieces for examples 11-14 were welded together at 130° C. for 17seconds to form a ring. The characteristics of the materials that wereused for skin and core of each example have been taken up in Table II.

Determination of Saturation Level

To determine the saturation level of etonogestrel of the polyethylenevinylacetate copolymers used, films of about 200 mm were prepared byfilm extrusion. The films were cut in pieces of 5×5 cm and subsequentlyimmersed in saturated aqueous solutions of etonogestrel at 25° C. After6 weeks of incubation, equilibrium was reached and the films wereanalyzed for the content of etonogestrel. The pieces were extracted withmethanol for 20 hours at a temperature of 70° C. and subsequently theconcentration of etonogestrel was assessed by HPLC, using a Novapak C18column of 3.9×150 mm at column temperature of 30° C., a mobile phase ofmethanol/water/THF (46/48/6 v/v %), a flow rate of 1.5 ml/min, and aninjection volume of 40 μl. Detection was carried out by UV detection at210 nm.

Fibre Dimension

The fibre dimensions (outer diameter and skin thickness) were determineddirectly after processing. The outer diameter was determined by means oflaser thickness gauge (Mitutoyo). The skin thickness was determinedusing a microscope (Jena).

Vinylacetate Content of the Copolymer

The vinylacetate content for the copolymers used in the examples 2-14 asspecified in II, IV, V and VI was determined by 1H NMR in a DRX600\NMRspectrometer (Bruker Spectrospin, Switzerland). For the NMR method 15-20mg of slices of about 3-5 mg originating from different parts of thesample were mixed with 0.7 ml of tetrachloroethane-d₂. Subsequently theNMR tube was heated in an oil bath during 15-18 hours at 100° C.Hereafter a proton spectrum was acquired at 90-100° C. with 128 scansand a D1 of 5 seconds to assure complete relaxation. The spectrum wasprocessed by applying an exponential multiplication of 0.3 Hz followedby Fourier transformation. The spectrum was integrated and the integralof the CHO(C═O)CH3 group was set at 1. The vinylacetate content wascalculated with formula I:

$\begin{matrix}{{{vinylacetate}(\%)} = {\frac{y*M_{VA}}{{\left\lbrack {\left( {x - {2*y}} \right)/4} \right\rbrack*M_{{{CH}\; 2} - {{CH}\; 2}}} + {y*M_{VA}}}*100}} & (I)\end{matrix}$

wherein:

x=integral CH2

y=integral CHO(C═O)CH3

M_(VA)=molecular weight VA (86)

M_(CH2-CH2)=molecular weight MCH2-CH2 (28)

With y set at 1 (see above) the formula is reduced to formula II:

$\begin{matrix}{{{vinylacetate}(\%)} = {\frac{86}{{\left( {x - 2} \right)*7} + 86}*100}} & ({II})\end{matrix}$

The measurement was performed in duplicate using two different samples.The vinylacetate content was calculated from the obtained spectrum.

In-Vitro Release Rate

The in-vitro release rate of etonogestrel for examples 1-14 wasdetermined by immersing the samples in 200 ml water of 37° C. undercontinuous stirring at 750 rpm. In order to maintain sink conditions thewater in the containers was refreshed daily by an auto-sampler. Theetonogestrel concentration was determined daily by HPLC, using a NovapakC18 column of 3.9×150 mm at column temperature of 30° C., a mobile phaseof acetonitril:water (30/70 v/v %), a flow rate of 1.5 ml/min, and aninjection volume of 10 μl. Detection was carried out by UV detection at205 nm. (see also the article of J. A. H. van Laarhoven et al.,International Journal of Pharmaceutics 232 (2002) pages 163-173).

Stability

The dimensions and the concentrations of active ingredients of theexamples are summarized in Table I and the characteristics of thematerial used is summarized in Table II. An overview of the releaseprofiles of etonogestrel for examples 1-14 and for the commerciallyavailable Nuvaring®, which is a product according to EP-A-0876815, aredepicted in FIG. 1.

Because of the concentration above the saturation level at 25° C.,etonogestrel in the samples of Nuvaring® and comparative example 1 mayeventually crystallize out onto the skin of the device, which isundesirable.

As illustrated by Table III and FIG. 1, examples 2-14 show that withdrug delivery systems according to the invention, which have aconcentration below saturation level at 25° C., a similar and sufficientrelease profile of etonogestrel for use in contraception and/or HRT isstill obtained.

TABLE I Description of the materials, concentrations and variables usedin examples 1-14. Fibre Skin Etono- Ethinyl Core Skin diameter thicknessgestrel estradiol Example material material (cm) (cm) (wt %) (wt %)Nuvaring ® Evatane ® Evatane ® 0.4 0.011 0.69 0.16 Comparative 28-251020 Comparative 1 Evatane ® Evatane ® 0.4 0.0083 0.69 0.13 33-25 1020 2Evatane ® Evatane ® 0.4 0.0042 0.4 0.075 33-25 1020 3 Evatane ®Evatane ® 0.5 0.0061 0.4 0.075 33-25 1020 4 Evatane ® Evatane ® 0.40.0091 0.4 0.075 33-25 1040 5 Evatane ® Evatane ® 0.4 0.0134 0.4 0.07533-25 1080 6 Evatane ® Evatane ® 0.4 0.0059 0.69 0.13 40-55 1020 7Evatane ® Evatane ® 0.4 0.0047 0.6 0.11 40-55 1020 8 Evatane ® Evatane ®0.5 0.0057 0.6 0.11 40-55 1020 9 Evatane ® Evatane ® 0.4 0.0099 0.6 0.1140-55 1040 10 Evatane ® Evatane ® 0.4 0.0152 0.6 0.11 40-55 1080 11Ateva ® Ateva ® 0.4 0.0084 0.6 0.10 4030 1525 12 Ateva ® Ateva ® 0.40.0036 0.4 0.075 3325 1070 13 Ateva ® Ateva ® 0.4 0.0065 0.4 0.075 33251231 14 Ateva ® Ateva ® 0.4 0.0099 0.4 0.075 3325 1525

TABLE II Description of the characteristics of the materials used inexamples 1-14. Vinyl- Saturation level Saturation level acetate ¹⁾ ofetonogestrel of etonogestrel Material (wt %) at 25° C. (wt %) at 37° C.(wt %) Evatane ® 28-25 ±28 0.35  0.44  Evatane ® 33-25 ±33 0.50  0.67 Evatane ® 40-55 ±40 0.75  1.12  Evatane ® 1020  ±9 0.046 0.055 Evatane ®1040 ±14 0.10  0.161 Evatane ® 1080 ±18 0.16* 0.21* Ateva ® 1070  ±9 0.045*  0.066* Ateva ® 1231 ±12  0.078*  0.107* Ateva ® 1525 ±15 0.12* 0.155* Ateva ® 4030 ±40 0.75*  1.126* Ateva ® 3325 ±33 0.50*  0.701* ¹⁾Vinylacetate content taken from product specification of the supplier*these saturation levels were obtained by interpolation from curve fitof the vinylacetate content of the material versus saturation level asshown in FIG. 2.

TABLE III Release rates for examples 1-14 Concentration VinylacetateVinylacetate R2 R21 above/below content of the content of the (μg/ (μg/Example saturation level core (wt %) skin (wt %) day) day) NuvaringAbove  28¹⁾   9¹⁾ 151.0 99.3 Comparative Comparative Above 34 10 154.5102.6  1  2 Below 34 10 140.7 81.3  3 Below 34 10 124.0 82.8  4 Below 3415 165.2 86.9  5 Below 34 20 207.3 91.9  6 Below 40 10 102.9 70.6  7Below 40 10 119.9 80.1  8 Below 40 10 117.9 86.1  9 Below 40 15 146.490.8 10 Below 40 20 184.4 101.1 11 Below 42 15 188.1 113 12 Below 32  9175.3 90 13 Below 32 11 147.0 82 14 Below 32 15 187.5 92 R2 and R21represent the release rates on day 2 and day 21 respectively.¹⁾Vinylacetate content for this sample was based on productspecification of the supplier

Burst Release

The extent of burst release is indicated by the burst release factor.The burst release factor was determined at t=0 with formula III:

$\begin{matrix}{\left( \frac{R_{1} - R_{2}}{R_{2}} \right)*100} & ({III})\end{matrix}$

wherein:

-   -   R₁ is release of the sample on day 1    -   R₂ is release of the sample on day 2.        The burst release factor of examples 1-14 was determined at t=0.        The results are shown in Table IV.

TABLE IV Results on the burst release at t = 0 of examples 1-14 Vinyl-Vinyl- Burst acetate acetate release Etono- content of content of Skinfactor at gestrel the core the skin thickness t = 0 ¹⁾ Example (wt %)(wt %) (wt %) (cm) (%) Nuvaring 0.69   28 ²⁾   9 ²⁾ 0.011 33.5Comparative Comparative 0.69 34 10 0.0083 18.6  1  2 0.4 34 10 0.004213.9  3 0.4 34 10 0.0061 15.0  4 0.4 34 15 0.0091 21.7  5 0.4 34 200.0134 26.3  6 0.69 40 10 0.0059 12.8  7 0.6 40 10 0.0047 11.7  8 0.6 4010 0.0057 12.7  9 0.6 40 15 0.0099 19.4 10 0.6 40 20 0.0152 24.0 11 0.642 15 0.0084 16.1 12 0.4 32  9 0.0036 16.1 13 0.4 32 11 0.0065 17.1 140.4 32 15 0.0099 22.9 ¹⁾ The burst release factor of Nuvaring, samples1-10 and samples 11-14 was based on the mean burst release factor ofrespectively 4, 3 and 6 samples. ²⁾ Vinylacetate content for this samplewas based on product specification of the supplier.

To exclude influence of the material of the core, only examples with asimilar etonogestrel and vinylacetate content in the core were compared.As illustrated in table IV, a drug delivery system with a relativelythin polyethylene vinylacetate copolymer skin having a relatively lowvinylacetate content results in an advantageously low burst release.

Flexibility

Furthermore the flexibility of examples 1-14 was determined and comparedwith the flexibility of Nuvaring®. The flexibility was determined bymeans of a press-pull apparatus (LR 5K, Lloyd Instruments). The entirering-shaped drug delivery system in a relaxed state was fixed in twoV-shaped holders. The distance between the corners of the V-shapedprofiles is 54 mm. Subsequently the holders were pressed towards eachother with a predetermined speed of 50 mm/min until the distance betweenthe corners of the V-shaped profiles was 21 mm. The force in Newton thatwas applied to the ring-shaped drug delivery system to bring about acertain deformation of the ring was measured at predetermined spots.That is, it was measured when the deformation comprised 10 mm (i.e. at adistance of 44 mm), 20 mm (i.e. at a distance of 34 mm), 30 mm (i.e. ata distance of 24 mm) and 33 mm (i.e. at a distance of 21 mm). Theresults are summarized in Table V.

TABLE V Flexibility results for examples 1-14 Vinylacetate Vinylacetatecontent of the content of the Fibre Skin core skin diameter thicknessForce at Force at Force at Force at Example (wt %) (wt %) (cm) (cm) 10mm(N) 20 mm(N) 30 mm(N) 33 mm(N) Nuvaring   28²⁾    9²⁾ 0.4 0.011 1.102.00 4.00 5.10 1 34 10 0.4 0.0083 0.78 1.37 2.90 3.82 2 34 10 0.4 0.00420.61 1.13 2.43 3.25  3* 34 10 0.5 0.0061 1.34 2.56 5.79 7.56 4 34 15 0.40.009 0.71 1.28 2.71 3.60 5 34 20 0.4 0.0134 0.72 1.30 2.82 3.73 6 40 100.4 0.0059 0.43 0.73 1.42 1.84 7 40 10 0.4 0.0047 0.40 0.69 1.35 1.75 8* 40 10 0.5 0.0057 0.77 1.37 2.81 3.76 9 40 15 0.4 0.0099 0.54 0.961.78 2.20 10  40 20 0.4 0.0152 0.56 1.05 2.14 2.78 11  42 15 0.4 0.00840.32 0.55 1.07 1.37 12  32  9 0.4 0.0036 0.54 1.02 2.34 3.17 13  32 110.4 0.0065 0.69 1.27 2.82 3.74 14  32 15 0.4 0.0099 0.67 1.24 2.78 3.73*Examples 3 and 8 show a relatively low flexibility due to the fact thatthe cross-sectional diameter of these fibres is 0.5 cm. For the fibreshaving the same cross-sectional diameter of 0.4 cm it can be concludedthat the ring-shaped drug delivery systems comprising a core with ahigher vinylacetate content show a much higher flexibility when comparedto Nuvaring ®. ²⁾ Vinylacetate content for this sample was based onproduct specification of the supplierRing Shaped Drug Delivery Systems Comprising a Skin Prepared fromPolypolyethylene Vinylacetate Copolymer with a High VinylacetateContent.

During storage, the polyethylene vinylacetate copolymer ages. Duringthis aging process crystalline and amorph domains in the polyethylenevinylacetate copolymer rearrange. As a result of the aging of thecopolymer, the release of active ingredients, here etonogestrel, canchange. The extent of aging of the copolymer is indicated by the Agingfactor. The Aging factor was determined with formula IV:

$\begin{matrix}{{Aging} = {\left( {1 - \frac{R_{2,{after\_ storage}}}{R_{2,{t = 0}}}} \right)*100\%}} & ({IV})\end{matrix}$

whereinR_(2,t=0)=Release on day 2 at t=0R_(2,after) _(—) _(storage)=Release on day 2 after the indicated storagetime

The aging behaviour for examples 1-10 and 11-14 has been tested underreal-time conditions (i.e. storage for 8 months at 20° C. respectively 3months at 25° C.) and under accelerated conditions (i.e. storage for 5months respectively 3 months at 40° C.). After storage the release ofetonogestrel on day 2 was determined and the aging factor calculated.The results are given in Table VI.

TABLE VI Aging for examples 1-10 after 5 months storage at 40° C.Vinylacetate Vinylacetate content of content of Skin R_(2, t=0)R_(2, t=5 mnd) Aging Etonogestrel the core the skin thickness (μg/day/(μg/day/ factor Example (wt %) (wt %) (wt %) (cm) sample) sample) (%) 10.69 34 10 0.0083 154.5 140.9 8.8 2 0.4 34 10 0.0042 140.7 130.4 7.3 30.4 34 10 0.0061 124.0 117.4 5.3 4 0.4 34 15 0.0091 165.2 159.2 3.7 50.4 34 20 0.0134 207.3 207.6 0 6 0.69 40 10 0.0059 102.9 91.3 11.3 7 0.640 10 0.0047 119.9 108.8 9.2 8 0.6 40 10 0.0057 117.9 105.6 10.5 9 0.640 15 0.0099 146.4 136.3 6.9 10 0.6 40 20 0.0152 184.4 183.3 0.6

To exclude influence of the material of the core, only examples with asimilar etonogestrel and vinylacetate content in the core are to becompared. The results in Table VI illustrate that after 5 months storageat 40° C., drug delivery systems with a relatively thick polyethylenevinylacetate copolymer skin having a relatively high vinylacetatecontent show less aging.

1-16. (canceled)
 17. A drug delivery system consisting of: (i) a corethat is comprised of: a thermoplastic polyethylene vinylacetatecopolymer containing 30 to 50 wt % vinylacetate; a progestogeniccompound, that is dissolved in the polyethylene vinylacetate copolymerat a concentration below the saturation level at 25° C., based on theweight of the core; and an estrogenic compound; and (ii) a skin that iscomprised of a thermoplastic polyethylene vinylacetate copolymer andthat covers the core, said skin being permeable to the progestogenic andestrogenic compounds; and wherein the drug delivery system is physicallystable when stored at a temperature ranging from about room temperatureto about 40° C.
 18. A drug delivery system according to claim 17,wherein the progestogenic compound is a steroidal progestogenic compoundand the estrogenic compound is a steroidal estrogenic compound.
 19. Adrug delivery system according to claim 17, wherein the progestogeniccompound is etonogestrel.
 20. A drug delivery system according to claim19, wherein the release on day 21 of etonogestrel of the drug deliverysystem is 80 μg/day or more.
 21. A drug delivery system according toclaim 17, wherein the estrogenic compound is ethinyl estradiol.
 22. Adrug delivery system according to claim 17, wherein the system isring-shaped.
 23. A drug delivery system according to claim 17, whereinthe drug delivery system is a drug delivery system for intravaginal use.24. A drug delivery system according to claim 17, wherein thepolyethylene vinylacetate copolymer of the skin is a copolymercontaining 1-15 wt % of vinylacetate.
 25. A drug delivery systemaccording to claim 24, wherein the skin has a thickness in the range of10 to 110 μm.
 26. A drug delivery system according to claim 24, whereinthe skin has a thickness in the range of 20 to 100 μm.
 27. A drugdelivery system according to claim 24, wherein the skin has a thicknessin the range of 30 to 70 μm.
 28. A drug delivery system according toclaim 17, wherein the polyethylene vinylacetate copolymer of the skin isa copolymer containing 14 to 28 wt % vinylacetate.
 29. A drug deliverysystem according to claim 28, wherein the skin has a thickness in therange of 70 to 250 μm.
 30. A drug delivery system according to claim 28,wherein the skin has a thickness in the range of 110 to 250 μm.
 31. Acontraceptive kit comprising the drug delivery system according to claim17.